Derivatives of dibenzo(b,f)pyrrolo(3,4-d)azepine as cns-depressants

ABSTRACT

COMPOUNDS OF THE CLASS OF 1,2,3,8-TETRAHYDRODIBENZO(B,F) PYRROLO (3,4-D) AZEPINES WHICH MAY BE SUBSTITUTED IN THE 5- OR 6- AND/OR 8-POSITION BY CHLORINE, THE TRIFLUOROMETHYL GROUP OR ALKYL GROUPS RESPECTIVELY OR THE ALLYL GROUP RESPECTIVELY AND PHARMACEUTICALLY ACCEPTABLE ADDITION SALTS THEREOF HAVE A DEPRESSANT EFFECT ON THE CENTRAL NERVOUS SYSTEM; THEY CAN BE PREPARED FROM THE CORRESPONDING N-SUBSTITUTED 10,11-BIS-BROMOMETHYL - 5H - DIBENZ (B,F) AZEPINES AND A PRIMARY AMINE; THE COMPOUNDS ARE ACTIVE INGREDIENTS OF PHARMACEUTICAL COMPOSITIONS.

United States Patent DERIVATIVES OF DIBENZO[b,f]PYRROLO[3,4-d] AZEPINEAS CNS-DEPRESSANTS Hans Blattner, Riehen, Switzerland, and WalterSchindler, deceased, late of Basel, Switzerland, by Leonhard Gysin,executor, Basel, Switzerland, assignors to Ciba-Geigy Corporation,Ardsley, N.Y.

No Drawing. Filed May 11, 1971, Ser. No. 142,390 Claims priority,appfication Switzerland, May 13, 1970, 7,069/ 70 Int. Cl. C07d 27/36 US.Cl. 260-3263 15 Claims ABSTRACT OF THE DISCLOSURE 7 DETAILED DESCRIPTIONThe present invention relates to new azepine derivatives, processes fortheir production, medicaments containing the new compounds, and theiruse.

More particularly, the present invention relates to compounds of theformula 2 l 1523 (iHz wherein R and R are hydrogen, alkyl groups havingat most 4 carbon atoms, or the allyl group,

X, is hydrogen, chlorine, or the trifluoromethyl group, and

X is chlorine if X is hydrogen, or hydrogen if X is chlorine or thetrifluoromethyl group.

and the pharmaceutically acceptable addition salts thereof. In thecompounds of Formula I R, and R; as alkyl groups having at most fourcarbon atoms are e.g., the methyl, ethyl, propyl, isopropyl, butyl,isobutyl or the scc.butyl group.

Preferred members of this class are:

2-ethyl-6-chloro-1,2,3,8-tetrahydro dibenzo[b,f]pyrrolo- [3 ,4-d]azepine Z-methyl 5 chloro 1,2,3,8 tetrahydro dibenzo [b,f]

pyrrolo 3,4-d] azepine 2-ethyl-6-chloro 8 methyl 1,2,3,8tetrahydrodibenzo- [b,rf]pyrrolo[3,4-d]azepineZ-methyl-S-chloro-8-methyl-1,2,3,8 tetrahydro dibenzob,f] pyrrolo[3,4-d] azepine ice and the pharmaceutically acceptable acid additionsalts thereof.

Compounds of the Formula I and the pharmaceutically acceptable acidaddition salts thereof have valuable pharmacological properties. Theyexert in particular after oral, rectal and parenteral administration acentral depressant action on the central nervous system. For examplethey reduce motility, potentiate the action of anaesthetics, andcounteract the effect of amphetamine. Moreover, they have an adrenolyticand histamineantagonistic action. These properties are determined byselected standard tests [cp. R. Domenjoz and W. Theobald, Arch. Int.Pharmacodyn. 120, 450 (1959), W. Theobald et al., Arzneimittelforsch.17, 561 (1967) and W Theobald and R. Domenjoz, Arzneimittelforsch. 8, 19(1958)].

Thus, merely by illustration, it is demonstrated that 2-methyl-S-chloro-1,2,3,8-tetrahydro dibenzo [b,f]pyrro1o- [3,4-d1azepinein the form of the hydrochloride salt effects a 50% decrease oforientation motility after intraperitoneal administration on mice in anamount of 0.77 mg./kg.

The same compound subcutaneously administered in an amount of 10 mg./kg.to mice, which had been anaesthetised by intraperitoneal administrationof 40 mg./kg. of the short-acting anaesthetic N,N-diethyl-2 methoxy 4-allyl-phenoxyacetic acid amide potentiates, i.e. prolongs the effect ofthe anaesthetic to a significant extent.

The same compound exerts an adrenolytic effectiveness which is foundequal to the activity of Regitin.

The same compound effects an antagonism against histamine which is foundequal to the activity of Antergan.

Similar results are found With 2-ethyl-6-chloro-1,2,3,8- tetrahydrodibenzo[b,f]pyrrolo[3,4 d]azepine, the 2- ethyl 6 chloro 8methyl-1,2,3,8-tetrahydro-dibenzo- [b,f]pyrrolo[3,4-d]azepine and the2-methyl-5-chloro-8- methyl l,2,3,8-tetrahydro dibenzo[bf]pyrrolo[2,4-d]azepine.

Although the hydrochloride salts are preferred, also otherpharmaceutically acceptable acid addition salts can be used.

The pharmacological properties of the compounds of the present inventionrender them suitable for the treatment of states of tension andagitation of psychic and muscular genesis.

The compounds of the Formula I are produced according to the inventionby reacting a compound of Formula II H BrEBrH \I a: pH

wherein:

R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or sec.butyl or agroup which by means of hydrolysis can be replaced by hydrogen, and

X and X have the meaning given under Formula I,

with an amine of the General Formula HI:

wherein R has the meaning given under Formula I, hydrolysing, thereaction product if R is a group which can be replaced by hydrogen bymeans of hydrolysis, and, optionally, converting an obtained compound ofthe general Formula I with an inorganic or organic acid into an additionsalt.

The bisbromomethyl compounds of the General Formula II are reacted withthe free bases of the General Formula III in the presence of a solvent.Suitable solvents are those which are inert under the reactionconditions, e.g. hydrocarbons such as benzene or toluene, halogenatedhydrocarbons such as chloroform, lower alkanols such as methanol orethanol, ethereal liquids such as ether or dioxane, as well as loweralkanones such as acetone, methyl ethyl ketone, or diethyl ketone. Thereaction temperature is preferably between 20 and 100 C. For the bondingof the hydrogen bromide eliminated in the reaction according to theinvention, an appreciable excess of base of the General Formula III ispreferably used.

Groups R convertible by hydrolysis into the hydrogen atom are, e.g. acylradicals, e.g. lower alkanoyl groups having preferably 1-4 carbon atoms,such as, e.g. the acetyl group, arenecarbonyl groups such as the benzoylgroup, radicals of monofunctional derivatives of carbonic acid such as,e.g. the methoxycarbonyl, ethoxycarbonyl, or the phenoxycarbonyl group.Hydrolysis can be performed with the aid of an alkali metal hydroxide,e.g. potassium or sodium hydroxide, preferably at the boilingtemperature of the reaction mixture, either in a higherboiling organicsolvent containing hydroxyl groups, such as, e.g. ethylene glycol ordiethylene glycol, or in a lower monoalkyl ether of such a glycol, and,in particular, in a lower alkanol, e.g. methanol or ethanol.Furthermore, hydrolysis may by performed, e.g. also in acid medium, e.g.in alkanolic hydrochloric acid, or with the aid of hydrogen bromide inwater or glacial acetic acid.

A group of starting materials of the General Formula II are compoundswhich are substituted in the -position by an acyl radical. A compoundfalling into this group is 2 chloro5-acetyl-10,1l-bisbromomethyl-SH-dibenz- [b,f]azepine. This compoundcan, for example, be produced as follows: Starting with2-chloro-9-methylacridine [cp. A. Campbell ct al., J. Chem. Soc.(London) 1958, 1145], this yields with acetaldehyde, in the presence oftert.-butyl hydroperoxide and ferrosulphate-heptahydrate:methyl-(2-chloro-9 methyl acridan 9 yl)- ketone; this ketone is reduced,with the aid of sodium borohydride, to2-chloro-a,9-dimethyl-9-acridanmethanol; the obtained reduction productis rearranged in dilute sulphuric acid according to Wagner-Meerwein togive 2- chloro-l0,ll-dimethyl-SH-dibenz[b,f]azepine, and dehydrated. Theobtained azepine derivative is acylated with acetic acid anhydride toobtain 2-chloro-5-acetyl-l0,1l-dimethyl-5H-dibenz[b,f]azepine, which issubsequently brominated with the aid of N-bromosuccinimide. Furthercompounds of the General Formula II which are substituted in 5-positionby an acyl radical can be produced analogously.

A second group of starting materials of the General Formula II arecompounds which are substituted in 5- position by a lower alkyl group.They can be produced, starting with a 2- or S-substituted9-methy1-10-alkylacridinium salt, by processes analogous to those forproducing the compounds of the first group of starting materials. Acompound contained in the second group is 2-chloro-5-methyl-l0,1lbisbromomethyl SH-dibeuz [b,f]azepine. It can be produced by thementioned process starting with a2-chloro-9,10-dimethyl-acridinium-halide by way of the intermediates:methyl-(2-chloro-9,10-dimethyl-acridanr9-yl )-ketone, 2-chloro-a,9,l0trimethyl- 9-acridanmethanol, and2-chloro-5,l0,1l-trimethyl-SH-dibenz[b,f]azepine.

A second process according to the invention for the production ofcompounds of Formula I comprises alkylating a compound of the FormulaIV:

wherein R X and X have the meaning given under Formula I, preferably inthe presence of solvents and basic condensation agents, by means of areactive ester of an alkanol of Formula V:

in which R has the meaning given under Formula I for R with theexception of hydrogen; and, if desired, converting the obtainedcompounds with inorganic or organic acids into their addition salts.

Starting materials of the General Formula IV can be produced analogouslyto the first process by reaction of 5-acyl-10,11-bisbromomethyl-SH-dibenz [b,f] azepine derivatives of the GeneralFormula II with an amine of the General Formula III, and hydrolysing theobtained acyl compound.

Used as the second reaction component are reactive esters of alkanols ofthe General Formula V. As reactive esters it is possible to use, e.g.halides usch as chlorides, bromides or iodides, sulphonic acid esterssuch as methanesulphonic acid ester, benzenesulphonic acid ester, 0- andp-toluenesulphonic acid ester or 2,4-dinitrobenzenesulphonic acid ester,as well as sulphuric acid ester such as dimethyl or diethyl sulphate.

The reaction according to the invention can be performed in the presenceor absence of an inert organic solvent. Suitable inert solvents are,e.g. hydrocarbons such as benzene, toluene, xylene, cumol or Tetralin,ethereal liquids such as dioxane, alkanones such as acetone or methylethyl ketone, carboxlyic acid amides such as dimethylformamide,phosphoric acid amides such as hexamethylphosphoric acid triamide, orsulphoxides such as dimethylor diethylsulphoxide. Suitable basiccondensation agents are, e.g. alkali metals such as sodium, potassium orlithium, alkali hydroxides such as sodium or potassium hydroxide, alkalimetal carbonate such as potassium carbonate, alkali metal amides such assodium-, potassiumor lithiumamide, alkali metal hydrides such as sodiumor lithium hydride, alkali metal alkanolates such as sodium methylate,sodium ethylate, or sodiumtert.butylate, or alkyland aryllithiumcompounds such as butylor phenyllithium. The reaction temperature ispreferably 0 to C.

A third process according to the invention for the production ofcompounds of the General Formula I comprises reducing a compound of theGeneral Formula VI:

l Hzi CHz X:

wherein R represents an alkanoyl group having at most 4 carbon atoms,and R X and X have the meaning given under Formula I,

by means of diborane in an etheral liquid; and converting the obtainedcompound of the General Formula I if desired into an addition salt withan inorganic or organic acid.

As the reaction medium can be used, e.g. tetrahydrofuran, dioxane,ethylene glycol dimethyl ether, or diethylene glycol dimethyl ether. Thereaction temperature is preferably between room temperature and ca. 100C., and the reaction duration between ca. 30 minutes and 25 hours. Thediborane is formed, e.g. from boron trifluoride-etherate and sodiumborohydride, either in a separate apparatus and then fed into thereaction mixture, or in situ.

The preparation of the starting materials of the General Formula VIwherein R as the alkanoyl group can be the formyl, acetyl, propionyl,butyryl, or isobutyryl group was described following the first process.

A fourth process according to the invention for the preparation ofcompounds of Formula I comprises hydrolysing a compound of the GeneralFormula VII:

H2O EH2 l h (VII) in which Ac is the acyl radical of an organic acid,and R X and X have the meaning given under Formula I;

and converting an obtained compound of the General Formula I, ifdesired, into an addition salt with an inorganic or organic acid.

In the starting materials of the General Formula VII, Ac is as an acylradical, in particular, the cyano or chlorocarbonyl group, an alkanoylor arenecarbonyl group, or the radical of a monofunctional derivative ofcarbonic acid, thiocarbonic acid, or dithiocarbonic acid. Mentioned asexamples are: for alkanoyl or arenecarbonyl groups the acetyl or benzoylgroup; for radicals of monofunctional derivatives of carbonic acid,thiocarbonic acid, or dithiocarbonic acid, the methoxycarbonyl,ethoxycarbonyl, tert.butoxycarbonyl, phenoxycarbonyl,benzoyloxycarbonyl, methoxythiocarbonyl, ethoxythiocarbonyl,methylthiocarbonyl, or the ethylthiothiocarbonyl group.

The hydrolysis of compounds of the General Formula VII is efiected, forexample, by several hours heating of such compounds in an alkanolic oraqueous-alkanolic alkali hydroxide solution, e.g. by boiling in amixture of potassium or sodium hydroxide with ethanol or metha- 1101 anda little water. Instead of lower alkanols, it is possible to use alsoother solvents containing hydroxyl groups, such as ethylene glycol orits lower monoalkyl ethers. Furthermore, it is possible to hydrolyse, inpartic-' ular, compounds of the General Formula VII wherein Ac is thecyano group also by heating with a mineral acid in organic-aqueous oraqueous medium, e.g. by several hours boiling in a mixture of 85%phosphoric acid and formic acid, or by several hours heating in 48%hydrobromic acid to ca. 60 to 120 C.

6 The starting materials of the General Formula VII are, in their turn,produced, e.g. from compounds of the General Formula VIII:

R4 1 1 HzC CHg X2 R1 (VIII) wherein R is a lower alkyl group, the allylor benzyl group, and R X and X have the meaning given under Formula I,

by allowing to act on the stated compounds, at room temperature or atelevated temperature, an organic acyl halide, e.g. a cyanogen halide,especially cyanogen bromide, also phosgene, a chloroformic acid alkylester, e.g. the chloroformic acid methyl ester, also the chloroformicacid phenyl ester or chloroformic acid benzyl ester, the chloride orbromide of a lower alkanoic acid or of benzoic acid, especially acetylchloride, acetyl bromide, or benzoyl chloride, whereby occurs accordingto the von Braun reaction the desired acylation with liberation of thealkyl, allyl or benzyl halide corresponding to the group R The reactionis carried out in an inert organic solvent such as, e.g. chloroform orbenzene or, optionally, also in an excess of an acyl halide suitable asreaction medium.

Compounds of the General Formula VIII can, on the other hand, beproduced analogously to the first process by reacting a compound of theGeneral Formula II with an amine of the General Formula 1X:

/R4 N-H wherein R, has the meaning given under Formula I.

The compounds of the General Formula I obtained by the processesaccording to the invention are, optionally,

r subsequently converted in the usual manner into their addition saltswith inorganic and organic acids. For example, to a solution of acompound of the General Formula I in an organic solvent is added theacid desired as salt component, or a solution of the acid. Preferablychosen for the reaction are organic solvents in which the formed salt isdifficulty soluble, so that it can be separated by filtration. Suchsolvents are, e.g. methanol, ether, acetone, methyl ethyl ketone,acetone/ ethanol, methanol/ ether, ethanol/ether, or methylene chloride/ethanol.

For use as medicaments it is possible to use, instead of free bases,pharmaceutically acceptable acid addition salts, i.e. salts with suchacids of which the anions are not toxic in the dosages in question. Itis moreover of advantage if the salts to be used as medicamentscrystallise well and are not, or only slightly, hygroscopic. For saltformation with compounds of the General Formula I it is possible to use,e.g. hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoricacid, methanesulphonic acid, ethanesulphonic acid,S-hydroxyethanesulphonic acid, acetic acid, malic acid, tartaric acid,citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid,maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelicacid, and embonic acid.

As previously mentioned, the new active substances are administeredorally, reactally, or parenterally. The dosage depends on the manner ofapplication, on the species, on the age, and on the individualcondition. The daily dosages of the free bases, or of pharmaceuticallyacceptable salts thereof, vary between 0.1 mg./kg. and 10.5 mg./k-g. forWarm-blooded animals. Suitable dosage units, such as drages, tablets,suppositories or ampoules, preferably contain -200 mg. of an activesubstance according to the invention, or of a pharmaceuticallyacceptable salt thereof.

Dosage units for oral administration contain, as active substance,preferably between 1 and 90% of a compound of the General Formula I, orof a pharmaceutically acceptable salt thereof. They are produced bycombining the active substance, e.g. with solid pulverulent carrierssuch as lactose, saccharose, sorbitol, mannitol; starches such as potatostarch, maize starch, or amylopectin, also laminaria powder or citruspulp powder; cellulose derivatives of gelatine, optionally with theaddition of lubricants such as magnesium or calcium stearate, orpolyethylene glycols, to form tablets or drage cores. The drage coresare coated, e.g. with concentrated sugar solutions which can alsocontain, e.g. gum arabic, talcum and/or titanium dioxide; or they arecoated with a lacquer dissolved in readily volatile organic solvents ormixtures of solvents. Dyestuffs may be added to these coatings, e.g. foridentification of different dosages of active substance.

Further suitable oral dosage units are hard gelatine capsules, as wellas soft closed capsules made from gelatine and a softner, such asglycerin. The hard capsules contain the active substance preferably as agranulate, e.g. in admixture with fillers such as maize starch, and/ orlubricants such as talcum or magnesium stearate, and, optionally,stabilisers such as sodium metabisulphite (Na S O or ascorbic acid. Insoft capsules, the active substance is preferably dissolved or suspendedin suitable liquids, such as liquid polyethylene glycols, wherebylikewise stabilisers may be added.

Suitable dosage units for rectal administration are, e.g. suppositoriesconsisting of a combination of an active substance, or of a suitablesalt thereof, with a suppository foundation substance. Suitable as asuppository foundation susbtance are, e.-g. natural or synthetictriglycerides, paraflin hydrocarbons, polyethylene glycols, or higheralkanols. Also suitable are gelatine rectal capsules consisting of acombination of the active substance, or of a suitable salt thereof, anda foundation substance. Suitable as a foundation substance are, e.g.liquid triglycerides, polyethylene glycols, or parafiin hydrocarbons.

Ampoules for parenteral administration, especially intramuscularadministration, preferably contain a watersoluble salt of an activesubstance in a concentration of preferably 0.5-5%, optionally togetherwith suitable stabilisers and buffer substances, in aqueous solution.

The following directions further illustrate the production of tablets,drages, capsules, suppositories, and ampoules:

(a) An amount of 250 g. of 2-ethyl-6-chloro-1,2,3,8- tetrahydrodibenzo[b,f] pyrrolo [3 ,4-d] azepine hydrochloride is mixed together with175.80 g. of lactose and 169.70 g. of potato starch; the mixture ismoistened with an alcoholic solution of g. of stearic acid, andgranulated through a sieve. After drying of the granulate, 160 g. ofpotato starch, 200 g. of talcum, 2.50 g. of magnesium stearate, and 32g. of colloidal silicon dioxide are mixed in, and the mixture is pressedto form 10,000 tablets each weighing 100 mg. and each containing mg. ofactive substance. The tablets can, if required, be provided with groovesfor a more precise adjustment of the dosage amount.

(b) A granulate is produced from 250 g. of 2-ethyl-6- chloro l,2,3,8tetrahydrodibenzo[b,f]pyrrolo[3,4 d] azepine hydrochloride, 175.90 g. oflactose, and the alcoholic solution of 10 g. of stearic acid. Afterdrying, the granulate is mixed with 56.60 g. of colloidal silicondioxide, 165 g. of talcum, 20 g .of potato starch, and 2.50 g. ofmagnesium stearate; the mixture is then pressed to form 10,000 dragecores. These are subsequently coated with a concentrated syrup made from502.28 g. of crystallised saccharose, 6 g. of shellac, 10 g. of gumarabic, 0.22 g. of dyestutf, and 1.5 g. of titanium dioxide. Afterdrying, the obtained drages each weigh 120 mg. and each contain 25 mg.of active substance.

(c) To produce 1000 capsules each containing 25 mg. of active substance,25 g. of 2-ethyl-6-chloro-l,2,3,8-tetrahydrodibenzo [b,f] pyrrolo 3,4-d]azepine hydrochloride are mixed with 248.0 g. of lactose; the mixture isthen evenly moistened with an aqueous solution of 2.0 g. of gelatine,and granulated through a suitable sieve (e.g. sieve III according to Ph.Helv. V). The granulate is mixed with 10.0 g. of dried maize starch and15.0 g. of talcum, and the mixture then evenly filled into 1000 hardgelatine capsules, size 1.

(d) A suppository foundation substance is prepared from 2.5 g. of2-ethyl-6-chloro-1,2,3,8-tetrahydrodibenzo [b,f]pyrrolo[3,4-d]azepinehydrochloride and 167.5 g. of adeps solidus; with this amount ofsubstance are then poured suppositories each containing 25 mg. of activesubstance.

(e) A solution of 25 g. of 2-ethyl-6-chloro-l,2,3,8-tetrahydrodibenzo[b,f] pyrrolo[3,4-d]azepine hydrochloride in one litre of water isfilled into 1000 ampoules, and then sterilised. An ampoule contains a2.5% solution of 25 mg. of active substance.

As active substance for tablets, drages, capsules, suppositories, andampoules it is also possible to use the same amount of the followingcompounds:

2-methyl-5-chloro-l,2,3,8-tetrahydrodibenzo [b,f]pyrrolo [3,4-d]azepinehydrochloride,

2, 8-dimethyl-5-chloro-1,2,3,8-tetrahydrodibenzo [b,f]

pyrrolo[3,4-d]azepine hydrochloride, and

2-ethyl-6-chloro-8-methyl-1,2,3,8-tetrahydrodibenzo[b,f]

pyrrolo [3 ,4-d azepine hydrochloride.

The following examples further illustrate the production of the newcompounds of the General Formula I and of intermediates not describedhitherto; the examples do not, however, limit in any way the scope ofthe invention. The temperatures are given in degrees centigrade, and thesilica gel used as an adsorbent is Silicagel Merck, particle size0.05-0.2 mm.

Example 1 (a) An amount of 20 g. (0.088 mol) of finely ground3-chloro-5H-dibenz[b,f]azepine (cp. J. R. Geigy A.G., French Pat.1,274,413) is refluxed in 600 ml. of 48% hydrobromic acid for 90minutes. The reaction mixture is then cooled with ice, whereby a portionof the formed 3-chloro-9-methyl-acridine-hydrobromide precipitates. Tothe obtained suspension are added in portions, with ice cooling, 450 ml.of concentrated ammonia, solution, and the mixture is extracted Withether. The ethereal solution is washed with water, and extracted with300 ml. of l N sulphuric acid. If the crude product precipitates assulphate, then it is again dissolved by the addition of water. The ethersolution is washed three times with water, and the washing watercombined with the acid extract. The aqueous acid solution is treatedwith active charcoal, filtered, and the light-yellow filtrate madealkaline with concentrated ammonia. The precipitated base is taken up inether; the ether solution is dried over magnesium sulphate, filtered,and concentrated in vacuo. The residue is taken up in hot hexane, thehexane solution purified with active charcoal, filtered, and thesolution concentrated by evaporation. The obtained3-chloro-9-methylacridine, M.P. l17118, crystallises out.

(b) An amount of 22.7 g. (0.100 mol) of the acridine derivative obtainedaccording to (a) is dissolved, by heating, in ml. of 2 N sulphuric acid.The solution is cooled, and diluted with 120 ml. of ice water; it isthen placed into an ice/sodium chloride bath, and to the solution areadded, at 9, 29 ml. (0.512 mol) of ice cold acetaldehyde. Thetemperature of the mixture rises to 15 C.; it is cooled, with stirring,to 8, and to it are added dropwise and simultaneously, with stirring, asolution cooled to 4 of 144 g. (0.520 mol) of ferrosulphateheptahydratein 480 ml. of water, and 60 ml. (0.450 mol) of 75%tert.butyl-hydroperoxide (Fluka) cooled to 2. The reaction solution isvigorously stirred during the addition, and the dropping rate soadjusted that the temperature in the reaction vessel remains between 10and 13. After addition of half the amount of the two reagents there isformed on the wall of the vessel a crust, which is removed. Aftercompletion of the dropwise addition, stirring is continued for a further15 minutes, whereby the internal temperature of the reaction vesselfalls to 3 The obtained brown suspension is extracted with methylenechloride, the extract Washed with water, dried over sodium sulphate, andconcentrated in vacuo. The residue is dissolved in 72 ml. of warmabsolute benzene; the solution is then cooled, filtered through a columnof 52 g. of silica gel, washed afterwards with 320 ml. of abs. benzene,and the benzene eluate concentrated by evaporation. The residue isrecrystallised from ether/hexane, whereupon the puremethyl-(3-chloro-9-methyl-acridan-9-yl)ketone melts at 116118.

(c) An amount of 27.4 g. (0.100 mol) of the ketone obtained according to(b) is dissolved in 500 ml. of methanol. The solution is cooled to 10;to the solution are then added in portions within 10 minutes, in an icebath and while stirring is maintained, 19.1 g. (0.500 mol) of sodiumborohydride. Stirring is continued for a further hour at 5 and thereaction solution then concentrated in vacuo to a Weight of 70 g. Theaddition of 6.6 ml. of water and some seed crystals effect, aftercooling in an ice bath, the commencement of crystallisation. Coolingwith ice continues, 100 ml. of water are slowly added, and the whole isallowed to stand for one hour at The crystals are filtered off undersuction, washed with water until neutral, and dried in vacuo overpotassium hydroxide. Thus crude 3-chloro-a,9-dimethyl-9-acridanmethanolis obtained.

(d) To a mixture cooled to room temperature of 200 ml. of concentratedsulphuric acid/ water (10:1) (volume ratios) are added within a quarterof an hour, with vigorous stirring, 27.4 g. (0.100 mol) of the hydroxycompound obtained according to (c). The hydroxy compound passes slowlyinto solution, which heats up to 30. 90 minutes after commencement ofthe addition is formed the clear solution, which is stirred for afurther 45 minutes. The solution is poured onto a mixture of 800' g. ofice, 1 litre of water, and 500 ml. of methylene chloride. The organicphase is separated, and the aqueous phase extracted with methylenechloride. The combined methylene chloride solutions are washed withwater, dried over sodium sulphate, and concentrated in vacuo. Theresidue is dissolved in abs. benzene, and the benzene solution added to55 g. of silica gel. The adsorbent is filtered off under suction, washedoutwith abs. benzene/ ethyl acetate (10: 1), and the filtrateconcentrated in vacuo. The residue is crystallised from ether/hexane,whereupon the pure 3 chloro 10,11-dimethyl-Hdibenz[ b,f]azepine, M.P.137-139", is obtained.

(e) An amount of 10.0 g. (0.039 mol) of the azepine derivative obtainedaccording to (d) is refluxed in 100 ml. of acetic anhydride for minutes.The excess acetic anhydride is distilled off under vacuo at 80; the redoil remaining behind is taken up in absolute benzene, and the solutionchromatographed on a column of 120 g. of silica gel. The column iswashed out with 300 ml. of abs. benzene, and eluted with abs.benzene/ethyl acetate (10:1). Concentration of the eluate in vacuoyields 3- chloro 5 acetyl-10,11-dimethyl-5H-dibenz[b,f] azepine, whichis used as crude product.

(f) An amount of 11.3 g. (0.038 mol) of the compound obtained accordingto (e) is dissolved in 110 ml. of carbon tetrachloride. To the solutionare added 13.7 g. (0.077 mol) of N-bromosuccinimide; the obtainedsuspension is exposed to two 200 Watt lamps, and refluxed for one hour.The reaction mixture is cooled, filtered, and the filtrate concentratedin vacuo. The residue is taken up in benzene, the small amount ofundissolved 10 succinimide removed by filtration, and the filtrateconcentrated in vacuo. The residue is dissolved in ether, the ethersolution treated with active charcoal, filtered, and concentrated invacuo. Thus amorphous 3-chloro-5-acetyl-10,11-bisbromomethyl-SH-dibenz[b,f]azepine is obtained.

(g) An amount of 17.4 g. (0.036 mol) of the compound obtained accordingto (f) is dissolved in 350 ml. of abs. benzene. This solution is cooled,and to it are added dropwise within 20 minutes, with stirring, ml. (0.51mol) of a 21% ethylamine solution in benzene. From the reaction solutionprecipitates ethylaminehydrobromide. The reaction mixture is stirred fora further 10 minutes, and is then filtered through purified diatomaceousearth. The excess ethylamine in the filtrate is evaporated off in vacuo,and the benzene solution remaining behind extracted with 1 Nhydrochloric acid. The acidified extract is treated with activecharcoal, filtered, and rendered alkaline with concentrated potassiumhydroxide solution. The crude 'base precipitates as oil. It is extractedwith ether, the ether extract washed neutral with water, dried overpotassium carbonate, and concentrated in vacuo. Thus crude 2 ethyl 6chloro 8 acetyl-1,2,3,8-tetrahydrodibenzo[b,f]pyrrolo[3,4-d]azepine isobtained.

(b) An amount of 10.9 g. (0.032 mol) of the compound obtained accordingto (g) is dissolved in 50 ml. of abs. ethanol. To the solution are added40 ml. of 20% ethanolic potassium hydroxide solution, the mixture isrefluxed for 3 hours, and then cooled. An amount of 6.16 g. oforange-coloured crystalline reaction product is filtered otf undersuction. To the filtrate is added 1 g. of powdered potassium hydroxide;the mixture, from which 70 ml. of ethanol are distilled ofi, is boiledfor one hour, and cooled. A second fraction of 1.53 g. of crude reactionproduct precipitates, and is filtered off With suction. The motherliquor is diluted with water, extracted with ether, and the ethersolution extracted with 2 N hydrochloric acid. The acidified extract istreated with active charcoal, filtered, and the filtrate made alkalinewith conc. potassium hydroxide solution. The precipitated base is takenup in ether, the organic phase separated, dried over potassiumcarbonate, and concentrated in vacuo. The residue, which is crystallisedfrom a little ether, yields a third fraction of 1.25 g. of reactionproduct. The combined crystallisates are recrystallised from benzene,whereupon pure 2-ethyl-6-chloro-1,2,3,8-tetrahydrodibenzo [b,f]pyrrolo[3,4-d]azepine, M.P. 193195 is obtained.

An amount of 7.57 g. (0.025 mol) of the obtained base is dissolved in300 ml. of Warm methylene chloride. To this solution are added 5.1 ml.of 5.2 N abs. ethanolic hydrochloric acid. The hydrochlorideprecipitates. It is filtered 01f under suction, washed with ether, anddried in vacuo, whereupon it melts, in a sealed tube at 23 8-240.

Example 2 An amount of 4.33 g. (0.014 mol) of 2-ethyl-6-chloro-1,2,3,8-tetrahydrodibcnzo[b,f]pyrrolo[3,4 d]azepine is dissolved in 50ml. of hexamethylphosphoric acid-triamide; to the obtained solution areadded 3.70 ml. (0.028 mol) of a 30% sodium amide suspension in toluene.The dark green solution is stirred for 30 minutes in a bath at 50,cooled, and separated in vacuo from the formed gas. To the solution isthen added dropwise within 5 minutes, with stirring, a solution of 0.95ml. (0.015 mol) of methyliodide in 5 ml. of hexamethylphosphoric acidtriamide, and stirring continues for a further 15 minutes. The brown-redcoloured reaction solution is poured onto ice, diluted With a largeamount of Water, and made alkaline with conc. sodium hydroxide solution.The crude base precipitates. It is extracted with ethyl acetate, theethyl acetate solution washed with water, and extracted with 2 Nhydrochloric acid. The acidified extract is treated with activecharcoal, rendered alkaline with conc. potassium hydroxide solution, andthe precipitated base extracted with ether. The ether extract is washedwith water, dried over potassium carbonate, and concen- 1 1 trated invacuo. Thus crude 2-ethyl-6-chloro-8-methyl- 1,2,3,8-tetrahydrodibenzo[b,f]pyrrolo[3,4 d] azepine is obtained. An amount of 3.0 g. (0.0096mol) of crude base is dissolved in ether. The ether solution is shakenwith 2 N ethereal hydrochloric acid, the precipitated yellowhydrochloride filtered off under suction, and dried in vacuo. It meltsat 169-171" and contains one equivalent of crystal water.

Example 3 (a) An amount of 22.8 g. (0.100 mol) of 2-chloro-9-methyl-acridine [cp. A. Campbell et al., J. Chem. Soc. (London) 1958,1145] is reacted, analogously to Example 1(b), in 35 ml. of 2 Nsulphuric acid and 65 ml. of ice water with 7.2 ml. (0.128 mol) ofacetaldehyde, 15 ml. (0.114 mol) of 75% tert.butyl-hydroperoxide and 36g. (0.130 mol) of ferrosulphateheptahydrate, dissolved in 120 ml. ofwater, to give methyl-(2-chloro-9-methylacridan-9-yl)-ketone, M.P.134-135 (from ether/ hexane).

(b) An amount of 3.11 g. (0.0114 mol) of the ketone obtained accordingto (a) is dissolved in 40 ml. of methanol. To the solution are added0.50 g. (0.013 mol) of sodium borohydride, and stirring is carried outfor one hour at room temperature. The reaction mixture is carefullyconcentrated in vacuo, and the residue taken up in 100 ml. of methylenechloride. To the methylene chloride solution is added some anhydrousmagnesium sulphate; the solution is then filtered and the filtrateconcentrated in vacuo. Thus crude2-chloro-a,9-dimethyl-9-acridanmethanol is obtained, which is furtherprocessed as crude product.

If the obtained compound is not further used straight away, it has to bestored at (c) An amount of 15.1 g. (0.055 mol) of the hydroxy compoundobtained according to (b) is stirred in 300 ml. of concentratedsulphuric acid/water (:3) (volume ratios) at room temperature until asolution is formed. The reaction mixture is then further stirred for 30minutes at the same temperature and then added, with stirring, to amixture of 700 ml. of 50% potassium hydroxide solution and 2 kg. of ice.The obtained suspension is diluted with water, so that the precipitatedpotassium sulphate dissolves, and the solution extracted with ether. Theether solution is washed with water, dried over magnesium sulphate, andconcentrated in vacuo. The residue is recrystallised from ether/hexaneto obtain 2-chloro-10,11-dimethyl-5H-dibenz[b,f]azepine, M.P. 137-138".

(d) Analogously to Example 1(e), 13.11 g. (0.051 mol) of the compoundobtained according to (c) are refluxed with 100 ml. of acetic anhydridefor minutes, and the obtained crude product is purified on silica gel.Thus 2-chloro 5 acetyl-10,1l-dimethyl-SH-dibenz[b,f] azepine isobtained, which is used as crude product.

(e) An amount of 13.50 g. (0.045 mol) of the crude product obtainedaccording to (d) is reacted, analogously to Example 1(f), with 17.7 g.(0.091 mol) of N-bromosuccinimide. The obtained crude product ispurified on a column of 150 g. of silica gel. As elution agent isfirstly used absolute benzene, which extracts a secondary product, andafterwards a mixture of abs. benzene/ethyl acetate (10:1). Thebenzene/ethyl acetate eluate is concentrated in vacuo, whereupon pureyellowish, amorphous 2- chloro-5-acetyl-10,1l-bisbromomethyl 5Hdibenz[b,f] azepine is obtained.

(f) Within 10 minutes are added dropwise, with stirring, 100 ml. (0.32mol) of 10% methylamine solution in benzene to 19.0 g. (0.040 mol) ofthe compound produced according to (e), which is dissolved in 200 ml. ofabsolute benzene, the solution being cooled with an ice bath. Thedropping rate is so adjusted that the reaction temperature is Stirringis carried out for a further minutes; the precipitated salt is filteredoff under suction, and the filtrate concentrated in vacuo. The residueis taken up in ether, and the ether solution extracted with 1 Nhydrochloric acid. The acidified extract is made alkaline withconcentrated potassium hydroxide solution, and the precipitated crudebase extracted with ether. The ether solution is dried over potassiumcarbonate, and concentrated in vacuo. Thus amorphous yellowish 2-methyl-5-chloro 8 acetyl 1,2,3,8 tetrahydrodibenzo[b, f] pyrrolo [3,4-d]azepine is obtained.

The product is affected by the air and should be stored in a cold stateunder nitrogen.

(g) An amount of 6.63 g. (0.020 mol) of the compound obtained accordingto (f) is dissolved in 50 ml. of abs. ethanol. To this solution areadded 4.60 g. of potassium hydroxide; the mixture is then refluxed for 5hours under nitrogen, and afterwards cooled to 0. The precipitatedorange coloured crystals (4.61 g.) are filtered off under suction,washed with a little ice cold ethanol, and dried. The filtrate isconcentrated in vacuo, the residue dissolved in ether, the ethersolution extracted with 2 N hydrochloric acid, and the acidified extractrendered alkaline with concentrated potassium hydroxide solution. Theprecipitated free base is taken up in methylene chloride, the methylenechloride solution dried over potassium carbonate, and concentrated byevaporation. The crystalline residue of 0.66 g. is combined with thefirst fraction of crystals, and the mixture dissolved in benzene; thesolution is treated with active charcoal, filtered, and concentrated.Thus2-methyl-5-chloro-l,2,3,8-tetrahydrodibenzo[b,f]pyrrolo[3,4-d]azepine isobtained, M.P. 210- 212.

An amount of 5.35 g. of the obtained base is dissolved in 200 ml. ofmethylene chloride. The solution is cooled and to it are added, withstirring, 3.60 ml. of 19.5% ethanolic hydrochloric acid. Thehydrochloride of the applied base precipitates. It is cooled with ice,filtered oil under suction, washed with a little methylene chloride,dried, and taken up in ethanol. The ethanol solution is treated withactive charcoal and concentrated by evaporation; the obtained crystalsbelow 0.01 mm. are then dried at whereupon the reddish hydrochloridemelts at 230-231".

Example 4 To 1.84 g. (0.0065 mol) of 2-methyl-5-chloro-l,2,3,8-tetrahydrodibenzo [b,f] pyrrolo[3,4-d]azepine, dissolved in 50 ml. ofhexamethylphosphoric acid triamide, are added 1.67 ml. (0.0125 mol) of a30% sodium amide suspension in toluene. The reaction mixture is stirredfor 30 minutes at 30; it is then cooled and separated in vacuo from theformed gas. With Water cooling are then added dropwise, with stirring,0.43 ml. (0.007 mol) of methyliodide dissolved in 5 ml. ofhexamethylphosphoric acid triamide. The reaction mixture is stirred fora further 15 minutes; to it are again added the same amount of sodiumamide suspension, and the mixture separated in vacuo from the formedgas; the addition of the same amount of methyliodide is then repeated,and stirring again proceeds for a further 15 minutes. The mixture isafterwards poured on to ice, and extracted with ether. Because of theformation of quaternary salts, the aqueous layer remains yellowcoloured. The ether solution is extracted with 2 N hydrochloric acid,the acidified extract made alkaline with concentrated potassiumhydroxide solution, and the precipitated base extracted with ether. Theether solution is dried over potassium carbonate, and concentrated byevaporation. The residue is chromatographed on a column prepared from 50g. of silica gel and abs. benzene, and the crude product eluted withchloroform containing 1% of ethanol. The eluate is concentrated invacuo, and the residue recrystallised from isopropanol, whereupon yellow2,8-dimethyl-5-chloro-l,2,3,8-tetrahydrodibenzo[b,f]pyrrolo[3,4-d]azepine,M.P. 178-190, is obtained.

Example 5 (a) An amount of 10.0 g. (0.038 mol) of3-trifiuoromethyl-9-methyl-acridine (cp. Smith Kline and FrenchLaboratories, US. Pat. 3,016,373) is dissolved in 200 ml. of glacialacetic acid and 150 ml. of 0.05 N sulphuric acid. The solution is cooledto to it are then added 11 ml. (0.195 mol) of acetaldehyde, and thewhole is cooled, in an ice/sodium chloride bath, again to 10.Simultaneously are then added dropwise within minutes from separatedropping funnels, whilst stirring is maintained, a solution of g. (0.198mol) of ferrosulphateheptahydrate in 180 ml. of water, and 23 ml. (0.175mol) of tert.butyl-hydroperoxide. The reaction mixture is stirred for afurther one hour at room temperature, then diluted with one litre ofwater, and extracted with ether. The ether extract is washed untilneutral with water and with a 10% sodium carbonate solution and water,dried over magnesium sulphate, and concentrated in vacuo. The residue istaken up in abs. benzene, the solution filtered through a column of 140g. of silica gel (Merck, grain size 0.05-0.2 mm.), and subsequentlyWashed with abs. benzene. The filtrate is concentrated in vacuo, and theresidue recrystallised from hexane. Thus obtained is yellowishmethyl-(3-trifluoromethyl-9- methyl-acridan-9-yl)-ketone, M.P. -126.

(b) An amount of 5.0 g. (0.016 mol) of the ketone obtained according to(a) is dissolved in 50 ml. of methanol; to the solution are then added0.760 g. (0.020 mol) of sodium borohydride, and the whole is stirred forone hour at room temperature. The reaction mixture is carefullyconcentrated in vacuo, and the residue taken up in 100 ml. of methylenechloride. To the methylene chloride solution is added some anhydrousmagnesium sulphate; the mixture is afterwards filtered, and the filtrateconcentrated in vacuo. Thus obtained is crude 3-trifiuoromethyl- (1,9dimethyl 9 acridan methanol, which is further processed as crudeproduct.

An amount of 5.00 g. (0.016 mol) of the obtained hydroxy compound isadded to a cooled mixture of 50 ml. of cone. sulphuric acid/water (10:1)(vol. ratio). The obtained suspension is stirred for 30 minutes,whereupon it changes into a solution. The red solution is stirred for afurther 30 minutes, and then poured on a mixture of ml. of 50% potassiumhydroxide solution and 800 g. of ice. The obtained suspension is dilutedin order to dissolve the precipitated potassium sulphate, and theobtained solution extracted with ether. The ether extract is washed withwater, dried over magnesium sulphate, and concentrated in vacuo. Theresidue is dissolved in hot hexane, the hot solution treated, forpurification, with active charcoal, and the suspension filtered. Thefiltrate is concentrated by evaporation, whereby 3-trifluoromethyl-10,1l-dimethyl 5H dibenz[b,f]azepine, M.P. 153-155", crystallises out.

(c) An amount of 17.0 g. (0.0588 mol) of this compound and 116 ml. ofacetic acid anhydride are refluxed for thirty minutes followed byevaporation in vacuo to dryness. The residue is taken up in toluene andthe solution obtained is evaporated in vacuo. This working-step isrepeated in order to remove the acid anhydride completely, whereby3-trifiuorornethyl 5 acetyl-10,11-dimethyl 5H dibenz[b,f]azepine isrecovered as a yellow amorphous substance.

((1) A mixture of 20.0 g. (0.0604 mol) of the compound obtained, 185 ml.of carbon tetrachloride and 27.6 g. (0.755 mol) of N-bromo-succinimideis refluxed for 6 hours under simultaneous irradiation with two 200-wattlamps. After cooling the reaction mixture is filtered and the filtrateis evaporated in vacuo, whereby a red oil is obtained which is taken upin benzene and filtered through a column of 300 g. of silica gel (Merck,0.05-02 mm. grain size). The filtrate is evaporated in vacuo, wherebypure 3-trifluoromethyl-S-acetyl-l0,1l-bis bromomethyl-5H-dibenz[b,f]azepine is recovered as a yellowish fo'am.

(e) To an ice-cooled solution of 20 g. (0.0408 mol) of the compoundobtained in ml. of benzene a solution of 75 ml. of a 19.6 percent(g./v.) solution of ethylamine in benzene is added dropwise in anitrogen atmosphere in the course of thirty minutes. The cooling bath isthen removed and stirring is continued for further thirty minutes atambient temperature, the precipitated ethylamine-hydrobromide isfiltered by suction and the filtrate is evaporated in vacuo. The residueis taken up with each 250 ml. of ether and water, the mixture is shakenthoroughly, the aqueous layer is separated and extracted with ether. Thecombined ether-extracts are extracted with three portions of each ml. of2 N hydrochloric acid. The combined acid aqueous extracts are renderedalcaline by means of cone. potassium hydroxide solution and the obtainedreaction mixture is extracted with two portions of each 100 ml. ofmethylenechloride. The organic layer is separated, dried over potassiumcarbonate and evaporated in vacuo, whereby 2-ethyl-6-trifluoromethyl-8-acetyl 1,2,3,8 tetrahydro dibenzo[b,f]pyrrolo[3,4-d] azepine is obtainedas a yellowish foam.

(f) An amount of 11.0 g. (0.0296 mol) of the compound prepared isdissolved in 55 ml. of 96% ethanol and refluxed together with 7.0 g.(0.125 mol) of potassium hydroxide for two hours under a nitrogenatmosphere. Then the reaction mixture is cooled in an ice-bath, wherebyyellow crystals precipitate which are filtered off by suction and washedwith ethanol followed by washing with ether. Thus2-ethyl-6-trifluoromethy1 1,2,3,8tetrahydro-dibenzo[b,f]pyrrolo[3,4-d]azepine is obtained as yellowcrystals.

M.P. 188-190": By working up the mother liquors an additional amount ofthe compound is obtained. M.P. of the pure compound: 194.

5.1 g. of the base obtained are converted to the hydrochloride accordingto Example 3 using 3 ml. of a 19.5% ethanolic hydrogen chloridesolution. Yellow crystals; M.P. 230-233".

Example 6 (a) 7.2 (0.0147 mol) of the compound prepared according toExample 5(d) are dissolved in 70 ml. of methylenechloride and cooled to20 in a dry nitrogen atmosphere. To this solution 45 ml. of a 10%solution of methylamine in benzene is added dropwise whilst stirring andthen stirring is continued for thirty minutes at ambient temperature.The reaction mixture is shaken with saturated aqueous sodium bicarbonatesolution, the organic layer is separated, dried over magnesium sulphateand evaporated in vacuo. The residue is taken up in 100 ml. of ether andthe solution prepared is washed with water followed by washing with twoportions of each 100 ml. of 2 N hydrochloric acid. The combined acidextracts are rendered alcaline by means of conc.sodium hydroxidesolution and the mixture is extracted with two portions of each 100 ml.of methylenechloride. The combined extracts are dried over magnesiumsulphate and evaporated in vacuo, whereby2-methyl-8-acetyl-6-trifluoromethy1-l,2,3, 8 tetrahydrodibenzo[b,f]pyrrolo[3,4-d]azepine is obtained as a white foam.

(b) An amount of 4.9 g. (0.0137 mol) of the compound obtained isdissolved in 26 ml. of 96% ethanol and refluxed under nitrogen with 3.3g. (0.059 mol) of potassium hydroxide for one hour. After cooling thereaction mixture in an ice-bath the precipitated crystals are filteredby suction, washed with little ethanol and water and dried, whereby 2methyl-6-trifluoromethyl-1,2,3,8-tetrahydrodibenzo[b,f]pyrrolo[3,4-d]azepineis recovered. Yellow crystals; M.P. 195l97.

To an ice-cold solution of 2.2 g. (0.070 mol) of this base in 77 ml. ofmethylenechloride 1.2 ml. of 19.5% ethanolic hydrochloric acid are addedand set aside for 30 minutes. The precipitate is then filtered bysuction and dried in vacuo, whereby the hydrochloride of the compound isrecovered. Red-brown crystals; M.P. 230234.

Example 7 (a) An amount of 14.6 g. (0.0307 mol) of the compound preparedaccording to Example 3(e) is dissolved in 200 ml. of benzene and 93 ml.of a 21% solution of ethylamine in benzene are added dropwise withstirring and external cooling. After working up the reaction mixtureaccording to Example 1(g) 2-ethyl-5-chloro-8-acetyl- 1,2,3,8tetrahydro-dibenzo[b,f]pyrrolo[3,4-d]azepine is obtained as a colourlessfoam which is stored under nitrogen.

(b) An amount of 5.0 g. (0.01475 mol) of the compound obtained isdissolved in 50 ml. of ethanol, 3.28 g. of potassium hydroxide are addedand the mixture is refluxed under nitrogen for 2% hours. After coolingthe reaction mixture the crystals formed are filtered by suction. Themother liquor is saponified against by the same Way using the sameamounts of potassium hydroxide and ethanol respectively, whereby anadditional crop of crystals is collected.

The combined crystal fractions are recrystallized from benzene wherebypure2-ethyl-5-chloro-l,2,3,8-tetrahydrodibenzo[b,f]pyrrolo[3,4-d]azepine isobtained. Yellow crystals; M.P. 202-204".

To a solution of 2.82 g. of the base in 100 ml. of methylene-chloride1.86 ml. of 19.5% ethanolic hydrochloric acid are added. After standingfor thirty minutes the crystals are filtered by suction andrecrystallized from ethanol under nitrogen, whereby the hydrochloride isobtained; light red crystals. M.P. 232235.

Example 8 (a) An amount of 25.0 g. (0.0525 mol) of the compound obtainedaccording to Example 1(f) is dissolved in 200 ml. of abs. benzene and112 ml. of a methylamine solution in benzene are added dropwise in thecourse of 10 minutes under external ice-cooling. The occurringsuspension is stirred for thirty minutes at ambient temperature and thenevaporated in vacuo to dryness. The residue is taken up with each 200ml. of ether and water, shaken thoroughly and then the aqueous layer isseparated whilst the organic layer is extracted with two portions ofeach 100 ml. of 0.5 N hydrochloric acid. The acid aqueous extracts arecombined, filtered with charcoal and rendered alcaline to pH 8 by meansof 2 N sodium hydroxide solution and saturated aqueous bicarbonatesolution. The occurring suspension is extracted with three portions ofeach 200 ml. of methylenechloride, the combined extracts are dried overpotassium carbonate and evaporated in vacuo. The crude base obtained isdissolved in chloroform and chromatographed through a column of thefive-fold amount of silica-gel (Merck 0.050.2 mm. grain size). Then thecolumn is washed with chloroform in order to remove impurities. Elutionis effected by means of chloroform, which contains 1-2% of methanol.

The eluate is evaporated to dryness whereby 2-methyl- 6-chloro-8-acetyl1,2,3,8 tetrahydro dibenzo[b,f]pyrrolo[3,4-d]azepine is obtained as acolourless amorphous substance.

(b) An amount of 7.50 g. (0.0234 mol) of this compound is refluxedtogether with 0.5 g. of potassium hydroxide and 50 m]. of ethanol fortwo hours under nitrogen. After cooling the crystals are filtered bysuction, washed with water and dried in vacuo. The filtrat isconcentrated, extracted with ether which is then evaporated in vacuo,whereby a further crop of crystals is recovered. Thus 2-methyl6-chloro-1,2,3,8-tetrahydrodibenzo[b,f]pyrrolo[3,4-d] azepine isobtained. M.P. 196- 198 5.96 g. of the base obtained are converted tothe hydrochloride according to Example 7(b) which is recrystallized froma methanol/ethanol mixture; orange crystals, M.P. 228-231 (subL).

Example 9 An amount of 14.50 g. (0.0152 mol) of the base obtainedaccording to Example 7(b) is dissolved in 100 ml. of hexamethylphosphoric acid triamide and then a suspension (0.0322 mol) of sodiumamide in toluene is added thereto under nitrogen. The mixture is stirredat a temperature of 50 for thirty minutes and little ammonia gas formedis removed in vacuo. A solution of 2.94 g. n-propyliodide in 5 ml. ofhexamethyl phosphoric acid triamide is added under external ice-coolingand stirring the reaction mixture at ambient temperature is continuedfor 15 minutes. 500 ml. of water are then added with caution followed byextracting the mixture with three portions of each 250 ml. of ethylacetate. The combined extracts are washed with three portions of each300 ml. of water, dried over magnesium sulphate and evaporated in vacuo.The remaining reddish oil is dissolved in chloroform and chromatographedthrough a column of silicagel (Merck 0.050.2 mm. grain size). Elution iseffected with chloroform containing 1% of methanol followed byevaporating the solution to dryness yielding a yellow oil whichcrystallises on standing. Thus 2-ethyl-5-chloro 8- n propyl 1,2,3,8tetrahydro dibenzo[b,f]pyrrolo[3, 4-d]azepine is obtained. M,P. 92.

4.85 g. of the base are dissolved in ml. of methylene chloride followedby adding 2.90 ml. of a 19.5% ethanolic hydrochloric acid solution.After standing for 10 minutes the solution is evaporated to dryness andthe residue is stirred with 40 ml. of ethyl acetate. The crystalsobtained are filtered by suction and dried in vacuo, which represent thehydrochloride of the base. M.P. 212-217".

Example 10 An amount of 5.0 g. (0.0169 mol) of the base preparedaccording to Example 1(h) is reacted with n-propyliodide according toExample 9. After working up a crude product is obtained which isdissolved in chloroform and purified through a column containing thetenfold amount of silicagel (Merck 0.050.2 mm. grain size). Impuritiesare removed from the column by washing with chloroform. Elution iseffected by treating the column with chloroform containing 1% ofmethanol. The solvent is evaporated in vacuo and the residue isrecrystallized from hexane whereby pure 2-ethyl-6-chloro-8-n-propyl-1,2,3,S-tetrahydro-dibenzo[b,f]pyrrolo[3,4 d]azcpine is obtained; yellowplatelets; M.P. 127-129.

3.65 g. of the base are converted to the hydrochloride according toExample 9; yellow crystals; M.P. 235238.

Example 11 An amount of 4.135 g. (0.01395 mol) of the base preparedaccording to Example 1(h) is reacted with allylbromide by the method ofExample 9, yielding a reddish viscous oil which is purified throughsilicagel yielding finally 2-ethyl-6-chloro-8-allyl 1,2,3,8 tetrahydrodibenzo[b,f]pyrrolo[3,4-d]azepine as a pale yellow oil.

3.60 g. of this base are converted to the hydrochloride analogously toExample 9; yellow crystals, M.P. 208- 211".

Example 12 An amount of 4.30 g. (0.0127 mol) of the compound obtainedaccording to Example 7(a) is dissolved in a mixture of 20 ml. oftetrahydrofurane and ml. of abs. ether; this solution is cooled with anice-bath and then 50 ml. of an 1 M solution of diborane intetrahydrofurane are added under a nitrogen atmosphere. The mixture isstirred for one hour at room temperature, diluted with 50 ml. of etherand then water is added cautiously until further addition does not causemore foaming. Then 30 ml. of 2 N hydrochloric acid are added, the wholemixture is shaken and the organic layer is separated, washed severaltimes with water and evaporated in vacuo to dryness. The residue whichis identified as being a borane-complex is refluxed with 100 ml. of 2 Nhydrochloric acid and 10 ml. of ethanol under nitrogen for 2% hours.After cooling the clear reaction mixture is extracted with ether and theaqueous phase is rendered alcaline to pH 8 with sodium bicarbonate. Ayellow emulsion is obtained which is extracted with three portions ofeach 50 ml. of methylenechloride, the combined extracts are dried overpotassium carbonate and evaporated to dryness in vacuo. The remainingyellow oil is dissolved in chloroform and chromatographed through acolumn of the ten-fold amount of silicagel (Merck 0.05-0.2 mm. grainsize). Elution is effected using chloroform containing 0.5% of methanolwhich, after evaporating to dryness, yields pure 2-ethyl-5- chloro 8ethyl-l,2,3,8 tetrah'ydro-dibenzo[b,f]pyrrolo- [3,4-d]azepine as ayellow oil.

In the event that the elution is carried out using chloroform whichcontains 1% of methanol after evaporating the solvents the compound2-ethyl-5-chloro-l,2,3,8-tetrahydro-dibenzo [b,f]pyrrolo[3,4 dlazepineas a side-product can be isolated. M.P. 202-204".

3.05 g. of the base which has been prepared as the main product isconverted to the hydrochloride according to Example 9. After evaporationof the solvents the residue is rubbed with ether in order to inducecrystallization. The crystals are filtered by suction and recrystallizedunder nitrogen from isopropanol. M.P. 23 8-242".

Example 13 An amount of 6.31 g. (0.0195 mol) of the compound preparedaccording to Example 3(f) is dissolved in 30 ml. of abs.tetrahydrofurane and 150 ml. of abs. ether and to this solution 78.5 ml.of an 1 M solution of diborane in tetrahydrofurane are added undernitrogen and external cooling with an ice bath. After five minutes thecooling bath is removed and the reaction mixture is stirred for one hourat ambient temperature. After adding 50 ml. of ether, 5 ml. of water areadded dropwise with caution, and when foaming has ceased further 50 ml.of water and ml. of 2 N hydrochloric acid are added. The organic layeris separated, washed with water and evaporated in vacuo completely. Theremaining borane-complex is refluxed under nitrogen with 150 ml. ofethanol for four hours. The cooled clear solution is then extracted withether; the aqueous phase is treated with charcoal and after filtrationit is rendered alcaline to pH 8 with cone. potassium hydroxide solutionand saturated sodium bicarbonate solution. An emulsion is formed therebywhich is extracted with three portions of each 100 ml. ofmethylenechloride, the organic layers are combined, dried over potassiumcarbonate and evaporated in vacuo, whereby a yellow oil is obtained.This is dissolved in chloroform and chromatographed through a columncontaining the ten-fold amount of silicagel (Merck 0.05-0.2 mm. grainsize). Elution is carried out with chloroform which contains 1% ofmethanol. After evaporation of the solution to dryness pure2-methyl-5-chloro-8-ethyl-1,2,3,8-tetrahydro-dibenzo[b,f]pyrrolo[3,4-b]azepine is obtained as a yellow oil.

3.43 g. of this base are converted to the hydrochloride according toExample 9. M.P. 218-222.

Example 14 (a) An amount of 5.50 g. (0.0177 mol) of Z-methyl-S- chloro 8formyl l,2,3,8 tetrahydro-dibenzo[b,f]pyrrolo-[3,4-d]azepine is reducedaccording to the method described in Example 12. After evaporation ofthe methylenechloride extract a crystalline residue is obtained, whichis recrystallized from isopropanol, whereby pure 2,8-dimethyl-5-chloro1,2,3,8 tetrahydro-dibenzo[b,f] pyri'olo[3,4-d]azepine is obtained.Yellow crystals: M.P. 175-190".

4.48 g. of the base obtained are converted to the hydrochlorideaccording to Example 9; pale yellow crystals. M.P. 206-214 (subl).

(b) The compound 2-methyl-5-chloro-8-formyl-1,2,3,S-tetrahydro-dibenzo[b,f]pyrrolo[3,4-d]azepine needed as startingmaterial for the process described under (a) is prepared as follows:

An amount of 1.0 g. (0.00392 mol) of 10,11-dimethyl-2-chloro-dibenz[b,f]azepine in 5 ml. of water-free formic acid isrefluxed for one hour followed by evaporation to dryness. The oilyresidue is chromatographed through a column of 10 g. of silica gel(Merck ODS-0.2 mm. grain size) using a benzene/ethyl acetate mixture(3:1) as solvent as well as eluent fluid. After evaporation of thesolvents 10,11 dimethyl-Z-chloro-5-formyl-dibenz[b,f]azepine is obtainedas a yellow foam.

(0) An amount of 0.853 g. (0.00301 mol) of the compound obtained isdissolved in 10 ml. of carbon tetrachloride and brominated with 1.17 g.(0.00662 mol) of N-bromo-succinimide at boiling temperature andsimultaneous irradiation with two 200 watt lamps. After cooling thereaction mixture the succinimide formed is filtered off and the filtrateis evaporated in vacuo, whereby the crude product is obtained as a brownfoam which is dissolved in benzene and chromatographed through a columnwith 10 g. of silicagel (Merck ODS-0.2 mm. grain size).

After elution of the column with benzene the solution obtained isevaporated to dryness yielding10,11-bis-bromomethyl-Z-chloro-S-formyl-dibenz[b,f]azepine as a yellowfoam.

(d) An amount of 1.0 g. (0.00266 mol) of the compound obtained isdissolved in 10 ml. of methylenechloride and to the solution 6.9 ml. ofa 10% solution of methylamine in benzene are added at a temperature of20. The mixture is then stirred for thirty minutes at room temperature,followed by extraction with saturated sodium bicarbonate solution. Theorganic layer is separated, dried over magnesium sulphate and evaporatedin vacuo. The residue is taken up in ml. of ether, the solution isfiltered and the filtrate is extracted with two portions of each 100 ml.of 2 N hydrochloric acid. The combined acid extracts are renderedalcaline to pH 8 with sodium hydroxide and sodium bicarbonate solutionfollowed by extracting the mixture with two portions of each 50 ml. ofmethylenechloride. The combined organic layers are dried over magnesiumsulphate and evaporated in vacuo whereby the crude product is obtainedas a colourless foam. This is dissolved in benzene and chromatographedthrough a column of 10 g. of silicagel (Merck 0.05-0.2 mm. grain size)followed by elution of the column with a chloroform/ methanol (100:1)mixture. The filtrate is evaporated to dryness yielding 2-methyl-5-chloro8-formyl 1,2,3,8 tetrahydrodibenzo [b,f]pyrrolo- [3,4-d1azepine asa colourless foam.

What we claim is:

1. A compound of the Formula I H2O on:

wherein R and R are hydrogen, alkyl groups having at most 4 carbonatoms, or the allyl group,

X is hydrogen, chlorine, or the trifluoromethyl group,

and

X is chlorine if X is hydrogen, or is hydrogen if X; is

chlorine or the trifluoromethyl group,

and the pharmaceutically acceptable acid addition salts thereof. J

2. The compound according to claim 1 which is '2-methyl 5 chloro 1,2,3,8tetrahydrodibenzo[b,f]pyrrolo- [3,4-d1azepine or a pharmaceuticallyacceptable acid ad dition salt thereof.

3. The hydrochloride of the compound of claim 2.

4. The compound according to claim 1 which is 2- methyl-chlor'o 8 methyl1,2,3,8 tetrahydro-dibenzo- [b,f]pyrrolo[3,4-d]azepine or apharmaceutically acceptable acid addition salt thereof.

5. The hydrochloride of the compound according to claim 4.

6. The compound according to claim 1 which is 2-ethyl- 6 chloro 1,2,3,8tetrahydro dibenzo[b,f]pyrrolo- [3,4-d]azepine or a pharmaceuticallyacceptable acid addition salt thereof.

7. The hydrochloride of the compound according to claim 6.

8. The compound according to claim 1 which is 2-ethyl- 6 chloro 8 methyl1,2,3,8 tetrahydro dibenzo- [b,f]pyrrolo[3,4-d]azepine or apharmaceutically acceptable acid addition salt thereof.

9. The hydrochloride of the compound according to claim 8.

10. The compound according to claim 1 which is 2- ethyl 5 chloro 8 ethyll,2,3,8 tetrahydro dibenzo- [b,f]pyrrolo[3,4-d]azepine or apharmaceutically acceptable acid addition salt thereof.

11. The hydrochloride of the compound according to claim 10.

12. The compound according to claim 1 which is 2- 20 ethyl 5 chloro1,2,3,8 tetrahydro dibenzo[b,f] pyrrolo[3,4-d]azepine or apharmaceutically acceptable acid addition salt thereof.

13. The hydrochloride of the compound according to claim 12.

14. The compound according to claim 1 which is 2- methyl 6 chloro1,2,3,8 tetrahydro dibenzo-[b,f] pyrrolo[3,4-d]azepine or apharmaceutically acceptable acid addition salt thereof.

15. The hydrochloride of the compound according to claim 14.

References Cited UNITED STATES PATENTS 3,636,046 1/1972 Blattner et al.260326.9

JOSEPH A. NARCAVAGE, Primary Examiner US. Cl. X.R.

